1. Academic Validation
  2. Dual-targeting hybrid peptide-conjugated doxorubicin for drug resistance reversal in breast cancer

Dual-targeting hybrid peptide-conjugated doxorubicin for drug resistance reversal in breast cancer

  • Int J Pharm. 2016 Oct 15;512(1):1-13. doi: 10.1016/j.ijpharm.2016.08.016.
Yuan Sheng 1 Yiwen You 1 Yun Chen 2
Affiliations

Affiliations

  • 1 Nanjing Medical University, Nanjing, 211166, China.
  • 2 Nanjing Medical University, Nanjing, 211166, China. Electronic address: [email protected].
Abstract

The extended use of doxorubicin (DOX) could be limited due to the emergence of drug resistance associated with its treatment. In addition to the overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), other mechanisms including Apoptosis evasion and tumor cell survival may also be important contributor to drug resistance. Within this context, targeting extracellular signal-regulated kinases (ERK), one of the principle protein molecules in cell Apoptosis has emerged as an attractive therapeutic concept. In this study, a dual-targeting hybrid peptide HAIYPRHGGCGMPKKKPTPIQLNP (T10-ERK), which is composed of ERK peptide inhibitor MPKKKPTPIQLNP, a thiol spacer (i.e., GGCG) and Transferrin Receptor (TfR)-binding peptide HAIYPRH, was designed. Then, this thiol-modified hybrid peptide was conjugated to DOXO-EMCH (6-maleimidocaproyl) hydrazone of DOX), forming a novel peptide-DOX conjugate T10-ERK-DOX. The structure and properties of this conjugate were characterized using (1)H NMR, mass spectrometry and HPLC. Using MCF-7/ADR cells as an in vitro model system and nude mice bearing MCF-7/ADR xenografts as an in vivo model, the ability of T10-ERK-DOX to reverse drug resistance was accessed as compared with free DOX and T10-DOX. As a result, T10-ERK-DOX demonstrated a much lower in vitro IC50 (20.8±1.1μM) and its in vivo extent of inhibition in mice was more evident (72.2±4.6%). Induction of various Apoptosis pathways was also observed. Furthermore, the potency of ERK peptide inhibitor to reverse drug resistance was individually assessed, given the pronounced efficacy of T10-DOX indicated by our previous work. The results provided evidence of its additive effect with T10-DOX, which leads to greater efficacy and less susceptibility to drug resistance. Finally, the success of multi-targeting strategy in the present study implied that multi-target drugs with rational design could be more promising in Cancer therapy.

Keywords

Doxorubicin; Drug resistance reversal; Dual-targeting hybrid peptide; ERK peptide inhibitor; Multi-target effect; TfR-binding peptide.

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